The present invention relates to 3-substituted and 2,3-disubstituted pyridine compounds which are useful as intermediates in the synthesis of pyridylsulfonylurea herbicides. The invention also relates to arylation of alcohols using a pyridinediazonium salt. More particularly the arylation process of the instant invention relates to the synthesis of 2,3-disubstituted pyridine compounds via anhydrous diazotization of 3-aminopyridines to form a diazonium salt intermediate that is then reacted with the appropriate alcohol to produce the desired product. The invention additionally relates to pyridine-3-diazonium salt intermediates.
Arylation reactions involving dediazotization of a diazonium salt have been used to introduce various groups on to an aryl ring. March et al., Advanced Organic Chemistry, 4th Ed., John Wiley and Sons, (1992), pages 721-725. Aromatic and heteroaromatic sulfides have been successfully prepared from primary aromatic and heteroaromatic amines by adding the appropriate amine to a solution of isopentyl nitrite and excess of dimethylsulfide which is heated to 80-90xc2x0 C. Giam et al., J. Chem. Soc., Chem. Commun., 1980, 756-757. Arylation of olefins by the combination of arylamines (such as 3-aminopyridine) and tert-butyl nitrite under palladium catalysis in the presence of acid has also been described in the chemical journal literature. Kikukawa et al., J. Org. Chem., 1981, Vol.46, 4885-4888. It is believed that the reaction of an arylamine and an alkyl nitrite gives an aryl radical under neutral conditions, whereas it affords a diazonium salt under acidic conditions. Replacement of the primary aromatic amino group by hydrogen has been accomplished by decomposing diazonium fluoborates in the presence of ethanol and zinc, however, when 3-aminopyridine is used, an additional by-product is obtained as the 3-ethoxypyridine in low yield (12.2%). Roe et al., J. Amer. Chem. Soc. 1952, Vol. 74, 6297-6298. 2-chloro-3-hydroxypyridine has been prepared by reacting 3-amino-2-chloropyridine with a nitrite in the presence of acid. Schickh et al., Berichte d. D. Chem. Gesellschaft, 1936, Vol. 69, 2593-2605.
The relative reactivity of aniline derivatives and primary aminopyridine compounds is not analogous in the context of diazotization and de-diazotization reactions. It would be overly simplistic to view the pyridine ring as analogous to a benzene (i.e. pyridine is not a benzene ring merely having a nitrogen ring atom therein). There is a dramatic difference in the reactivity of benzene and pyridine moieties that is caused by the presence and electronic effects of the nitrogen in the ring of the latter. Similarly, there may be significant differences in the stability of the corresponding benzenediazonium salts and pyridinediazonium salts containing these moieties. Additionally, 3-aminopyridine moieties are not functionally equivalent to 2-aminopyridine moieties when considered in the context of diazotization-dediazotization reactions. The electronic effects and chemistry are completely different for the diazonium salts prepared from 2-aminopyridines as compared to the diazonium salts prepared from 3-aminopyridines. The most relevant difference is that pyridine-2-diazonium salts are very unstable and can not be isolated. See Heterocyclic Compounds, Volume 14, supplement part 3, page 74 (1974) and R. N. Butler, Chemical Reviews, 1975, Volume 75, No. 2, page 250.
What is commonly observed when a diazonium salt is treated with an alcohol is reduction of the diazonium salt (ArN2+) to the ArH species. For a general discussion of diazonium chemistry see Nathan Kornblum, Organic Reactions, Volume 2, page 262 (1944). Surprisingly, it has now been discovered that the use of halogenated alcohols yields the corresponding alkoxide as the major product.
One embodiment of the invention is the compounds of formula I: 
wherein R1 is a C1-C4 haloalkyl and R4 is H, halogen or C1-C4 alkylthio; and acid addition salts thereof. The haloalkyl groups may be branched or unbranched. The halogen(s) of the haloalkyl group and R4, when halogen, are independently selected from fluoro, chloro, bromo and iodo. The degree of halogen substitution of R1 may range from monohalogen substitution to polyhalogen substitution wherein all the hydrogens of the alkyl group have been replaced by halogens (e.g. perfluoroalkyl groups). Compounds of formula Ia constitute preferred embodiment of the invention: 
wherein R1 is defined as above. Another preferred embodiment of the invention is wherein R1 is selected from the group consisting of xe2x80x94CH2CF3, xe2x80x94CH2CCl3, and xe2x80x94CH2CH2Cl. An ultimately preferred embodiment of the invention is the compound having the formula: 
2-chloro-3-(2,2,2-trifluoroethoxy)pyridine.
Another aspect of the invention is the pyridinediazonium salt of formula II: 
wherein Axe2x88x92 is a counter-anion derived from an organic acid or inorganic mineral acid, HA; and R4 is defined as above. Axe2x88x92 is preferably an anion of the formula xe2x88x92OSO2R2 (i.e. the conjugate base of a sulfonic acid), wherein R2 is C1-C4 alkyl, phenyl, C7-C10 alkylaryl, or C5-C10 cycloalkyl (preferably methyl); or an anion of the formula OOCxe2x80x94R2a (i.e. the conjugate base of a carboxylic acid) wherein R2a is C1-C4 haloalkyl, preferably trifluoromethyl; and R4 is defined as above. The pyridinediazonium salt of formula II is useful as an intermediate for the preparation of the compounds of formula I.
A preferred pyridinediazonium salt is the pyridinediazonium sulfonate salt of formula IIxe2x80x2: 
and formula IIaxe2x80x2: 
wherein R2 and R4 are defined as above. A preferred feature of the invention is where R2 is methyl or a 10-camphoryl group (i.e. a pyridinediazonium 10-camphorsulfonate salt).
Another aspect of the invention is the product produced from the process of diazotizing a 3-aminopyridine with an alkyl nitrite and acid under substantially anhydrous conditions. The pyridinediazonium salt of formula II or the product from the process of diazotization (to the extent there is a difference) are both features of the instantly disclosed invention. The scope of the invention as to the diazonium salts and the process of preparing the compound of formula I disclosed herein should not be construed to be limited by any particular chemical theory relating to the complexation, equilibration, reaction or acid-base chemistry of the components used to make the diazonium salt or the final product. Another aspect of the invention is pyridinediazonium salts of formula II wherein said salt has interacted chemically so as to result in a changed form of the salt or has interacted with other chemical components so as to form another more stable compound or acid addition salt thereof. Accordingly, the present invention encompasses the substantially unaltered static composition of the appropriate components as well as the chemically integrated composition. xe2x80x9cStatic compositionxe2x80x9d denotes 1) the composition composed of components wherein the components have not substantially changed by virtue of their combination or interaction with other composition components, or 2) the composition that has reacted to a point of relative stasis. xe2x80x9cChemically integrated compositionxe2x80x9d means a composition that results from any equilibration, complexation, dissociation or other chemical transformation (if any) that may occur after combination of the reagents used to prepare the product composition containing the salts of formula II and prior to ultimate use for the preparation of the compounds of formula I. Therefore, the xe2x80x9cchemically integrated compositionxe2x80x9d of the instant invention by definition encompasses the situation where there is an unchanged xe2x80x9cstatic compositionxe2x80x9d as well as the equilibrated or semi-equilibrated composition existing at any point between initial creation and ultimate use. In other words, the disclosed invention relating to diazonium salts is not limited to a static composition of chemically unaltered constituent components.
The invention also includes the process for obtaining the salts of formula II which are useful as intermediates in the process of preparing the compounds of formula I.
The compounds of formula I are prepared by reacting a salt of formula II under substantially anhydrous conditions with an alcohol having the formula R1OH wherein R1 is defined above. A preferred process of preparing the compounds of formula I comprises reacting a 3-aminopyridine with an alkyl nitrite in the presence of acid and a solvent/reagent alcohol that reacts with the diazonium salt intermediate generated in situ thereby forming the desired product without isolating the intermediate salt of formula II. See Schemes I and II below.
Scheme I 
wherein R3 is C1-C5 alkyl, and R1 and R4 are defined as above.
Scheme II 
The Variables in Scheme II are as Defined Above
The single-step or xe2x80x9cone-potxe2x80x9d procedure depicted in Schemes I and II may be accomplished by adding the alkyl nitrite, preferably t-butyl nitrite, directly to a hot (i.e. 50xc2x0 C. to 75xc2x0 C.) solution of the appropriate 3-amino-pyridine and from 0.5 to 2 equivalents of acid, preferably one equivalent of acid, preferably methanesulfonic acid, in the desired alcohol R1OH, preferably 2,2,2-trifluoroethanol thereby generating the desired 3-substituted-pyridine product. An excess amount of the alcohol may be used so that it thereby acts additionally as the solvent in the reaction. Other solvents may be used such as methyl-tertiary-butyl ether (MTBE) or chloroform, either alone or in combination with an alcohol solvent. The solvent or excess alcohol may be removed by distillation, evaporation, under vacuum or otherwise separated from the product using conventional means known in the art.
One of ordinary skill in the art would realize the costs and benefits of preparing the compounds by a xe2x80x9cone-potxe2x80x9d or single-step procedure as compared to a two-step procedure wherein the intermediate salt of formula II is heated, transferred to another reaction vessel, purified or otherwise isolated prior to being used in the subsequent dediazotization reaction. Schemes III and IV (below), depict two-step procedures that may be used to make the compounds of formula I and Ia, respectively.
Scheme III 
The Variables in the Scheme III are as Defined Above
Scheme IV 
The Variables in the Scheme IV are as Defined Above
The two-step procedure depicted in Schemes III and IV may be carried out by dissolving the appropriate 3-aminopyridine in the desired alcohol, R1OH, preferably 2,2,2-trifluoroethanol, in the presence of 0.5 to 2 equivalents acid, preferably one equivalent of acid, preferably methanesulfonic acid. However, other solvents such as MTBE or chloroform may also be used alone or in combination with an alcohol solvent. The alkyl nitrite, preferably t-butyl nitrite, is then added slowly to the 3-aminopyridine solution, preferably at 0xc2x0 C., thereby generating a diazonium salt. The diazonium salt solution is then either heated followed by addition of the desired alcohol, R1OH or the solution is added directly without heating to a hot solution of the desired alcohol, R1OH thereby generating the 3-substituted-pyridine product. The solvent or excess alcohol may be removed by distillation, evaporation, under vacuum or otherwise separated from the product using conventional means known in the art.
The ultimate starting materials, such as 3-amino-2-chloropyridine are either commercially available, may be prepared by known procedures or otherwise may be prepared using conventional chemistry knowledge. Similarly, the alkyl nitrite, acid and alcohol reagents are commercially available, may be prepared by known procedures or may otherwise may be prepared using conventional chemistry knowledge. For example, t-butyl nitrite or isoamyl nitrite are two commercially available nitrites that can be used in the instant invention.
By xe2x80x9calkylarylxe2x80x9d is meant an aryl group substituted by one or more alkyl groups, wherein the xe2x80x9carylxe2x80x9d may be either a non-heteroaromatic ring system or heteroaromatic ring system.
By xe2x80x9caddition saltsxe2x80x9d are meant salts of a given compound (or salt) of the invention derived from the chemical interaction with inorganic acids or organic acids. Acid addition salts may also be adducts with an organic solvent or water.
Examples of acid addition salts derived from inorganic acids include hydrochlorides, hydrobromides, hydroiodides, sulfates, hydrogensulfates, phosphates, monohydrogenphosphates, dihydrogenphosphates, nitrates, and thiocyanates. Examples of acid addition salts derived from organic acids include carboxylates, sulfonates, and phosphonates. Examples of acid addition salts derived from a carboxylic acid include formates, acetates, propionates, butyrates, cinnamates, benzoates, lactates, oxalates, malonates, succinates, glutarates, adipates, maleates, fumarates, phthalates, citrates, tartarates, salicylates, nicotinates, mandelates and salts from amino acids. Examples of acid addition salts derived from a sulfonic acid include alkylsulfonates (e.g. methanesulfonates, benzenesulfonates (e.g. p-toluenesulfonates), naphthlenesulfonates and camphorsulfonates. Examples of acid addition salts derived from a phosphonic acid include alkylphosphonates (e.g. methylphosphonates) and benzenephosphonates (e.g. phenylphosphonates).
xe2x80x9cSubstantially anhydrous conditionsxe2x80x9d is defined as conditions sufficient to conduct the diazotization or dediazotization without an undesirable decrease in the efficiency of the process while taking into account the costs and benefits of obtaining the appropriate reagents and reactor design. Preferably, the diazotization or dediazotization reactions are conducted in the absence of water.
The compounds of formula I are useful as intermediates for preparing pyridylsulfonylureas which are ultimately useful as herbicides and plant-growth regulators. For example, Schemes V and VI illustrate certain synthetic routes wherein 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine is used as an intermediate for the production of a known pyridylsulfonylurea which is useful as an herbicide for controlling weeds in corn and sugar cane crops. See U.S. Pat. Nos. 5,403,814 and 5,579,583 which are hereby incorporated by reference. The individual transformations in Schemes V and VI may be accomplished by using means generally known to one of ordinary skill in the art. See for example U.S. Pat. Nos. 5,403,814 and 4,522,645, and EP-A-103543, which are hereby incorporated by reference.
Scheme V 
Scheme VI 
The compounds of formula I wherein R4 is hydrogen can also be used to make the compounds of formula I wherein R4 is a chloro or bromo. The synthetic transformation may be accomplished via an electrophilic aromatic substitution reaction. Typical chlorinating reagents that may be used are FeCl3, AlCl3, N-chlorosuccinimide or SO2Cl2. Typical brominating reagents that may be used are FeBr3 and N-bromosuccinimide. The reactions preferably are run in the absence of light.